Signal mining and risk analysis of Alprazolam adverse events based on the FAERS database

This study aims to evaluate the safety of Alprazolam by analyzing the FAERS database, provide data analysis for monitoring adverse drug reactions. This research encompasses adverse event (AE) reports related to Alprazolam from the first quarter of 2004 to the second quarter of 2023. Four signal mining and analysis methods were utilized, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Further exploration was conducted regarding patient characteristics and types of AEs. A total of 23,575 AE reports in which Alprazolam was the primary suspect drug were collected, identifying 347 Preferred Term (PT) signals and 27 System Organ Classes (SOCs). The number of AE reports increased annually, especially in 2015, 2018, 2019, and 2020. The main affected groups were females and the age range of 18 to 45. Psychiatric disorders, Nervous system disorders, and Gastrointestinal disorders were the most common the organ system in which the AEs occurred. There is a certain risk of drug abuse and suicide with Alprazolam. Most notably, several AEs not recorded in the Alprazolam leaflet appeared among the top 30 PTs in signal strength, including but not limited to Benzodiazepine drug level abnormal, Acquired amegakaryocytic thrombocytopenia, Cutaneous T-cell dyscrasia, and Coronary No-reflow Phenomenon. For the first time, AEs related to the cardiovascular system and platelet function were unveiled. The severe AE reports that resulted in "hospitalization" and "death" accounted for 30.96% and 21.86%. This study highlights the risks of suicide and misuse of Alprazolam. Other potential severe or fatal AEs, such as those related to the cardiovascular system, platelet function, and others, require further research to determine their precise mechanisms and risk factors.

Alprazolam may induce psychomotor disorders and cognitive degeneration.It's also possibly correlated with increased risks of Alzheimer's disease, strokes, and malignant brain tumors 7,8 .Additionally, due to its unique pharmacokinetics (high potency, short half-life, rapid absorption and withdrawal effects), Alprazolam manifests a higher propensity for abuse, potentially triggering withdrawal syndromes more severe than other BZDs, thereby negatively impacting health and quality of life 9 .
To better understand the safety profile and inherent risks of Alprazolam, and to deliver a more comprehensive insight to underpin prudent medicinal decisions, this study delves into AE data associated with Alprazolam in FAERS.It aims to unearth safety signals and risk factors through a meticulous analysis, thoroughly probing patterns, trends, and correlated factors of Alprazolam's AEs.

Data source
The data for this study was sourced from the FAERS database.FAERS collects spontaneous safety reports and post-marketing clinical study reports related to drug use both within and outside the United States.This study selected data from the first quarter of 2004 to the second quarter of 2023.Analysis was performed using MySQL, and after deduplication, AE reports where Alprazolam was the primary suspected drug were obtained.

Data processing
Using "Alprazolam" as the keyword for retrieval from the database, we obtained details including personal information, drug information, AEs, and primary diseases.Following the FDA-recommended method for removing duplicate reports, we select the PRIMARYID (Primary Identification), CASEID (Case Identification), and FDA_DT fields from the DEMO table.We sort by CASEID, FDA_DT, and then PRIMARYID.For reports with the same CASEID, we retain the one with the largest FDA_DT value.FDA_DT refers to the FDA received date of the adverse event report.The rationale is that the report with the most recent received date likely contains the most up-to-date and complete information for that case.Secondly, for reports where both CASEID and FDA_DT are the same, we retain the one with the largest PRIMARYID value.PRIMARYID is a unique identifier assigned to each report.By keeping the report with the largest PRIMARYID, we aim to preserve the most complete data.Since the first quarter of 2019, each quarterly data package has included a list of deleted reports.After data deduplication, we remove reports based on the CASEID listed in the deleted reports list.The "Medical Dictionary for Regulatory Activities" (MedDRA) version 23.0 was used for AE terminologies.This included preferred SOC (System Organ Class) and PT (Preferred Term) for classifying and expressing AEs 10 .

Data analysis
Signal detection for AEs is essentially determining whether the reporting frequency of a specific AE for the target drug is higher than expected, thus establishing a statistical association between the drug and that specific AE.This study employed the Reporting Odds Ratio (ROR) 11 , Proportional Reporting Ratio (PRR) 12 , Bayesian Confidence Propagation Neural Network (BCPNN) 13,14 , and the Empirical Bayesian Geometric Mean (EBGM) 15 through SAS 9.4 software.The ROR helps mitigate biases in events with fewer reports.The PRR stands out for its greater specificity compared to ROR.BCPNN is adept at combining and cross-validating multi-source data.The MGPS is particularly effective in identifying signals from infrequent events.This study utilizes a blend of ROR, PRR, BCPNN, and MGPS to capitalize on their individual strengths, enhancing the scope of detection and validation from diverse angles.This integrated approach aids in more accurately identifying safety signals, reducing false positives through cross-validation and refining detection of rare adverse reactions by adjusting thresholds and variance.These methods are based on a 2 × 2 contingency table, as shown in Table 1.The formulas for each method and the conditions that satisfy signal generation are presented in Table 2.

Constituent ratio of yearly data
In this study, from January 1, 2004 to June 30, 2023, a total of 19,932,732 AE reports were obtained.Among them, 23,575 reports suspected Alprazolam as the primary drug.After analysis using the ROR, PRR, BCPNN, and EBGM methods, 347 signals on the PT level and 27 signals on the SOC level were detected.Female subjects dominated the AE reports for Alprazolam, accounting for 56.53%, while males accounted for 35.84%.Reports covered patients of all age groups, with the 18 to 45 age bracket having the highest proportion at 27.86%.Reports of AEs related to Alprazolam have shown an increasing trend year by year from 2004 to 2023.Notably, in 2015, 2018, 2019, and 2020, there was a significant increase in the number of reports, accounting for 8.97%, 10.52%, 13.86%, and 13.76% of the total reports, respectively.Consumers were the primary reporters, making up 35.37% of the total reports.The majority of reports came from the USA (54.43%), followed by France (18.57%) and  3).

Risk signal analysis results
In Table 4, the SOCs with many signals included: Psychiatric disorders, General disorders and administration site conditions, Nervous system disorders, Injury, poisoning and procedural complications, Gastrointestinal disorders.Among them, General disorders and administration site conditions, Injury, poisoning and procedural complications, Respiratory, thoracic and mediastinal disorders, Musculoskeletal and connective tissue disorders, Vascular disorders had a large number of reports.
In Table 5, among the top 30 PTs by report count, most were common adverse reactions for psychiatric drugs.Drug abuse, Drug dependence, Overdose, and Withdrawal syndrome had high occurrence rates.The suicide risk has also been detected, including Completed suicide, Suicide attempt, and Suicidal ideation.
In Table 6, the top 30 PTs by signal strength included many adverse reactions not recorded in the Alprazolam leaflet.Among them, Benzodiazepine drug level abnormal, Acquired amegakaryocytic thrombocytopenia, Postnatal growth restriction, Prescription form tampering, Papillary muscle disorder ranked the top five, being new potential adverse reactions.Additionally, even though Cutaneous T-cell dyscrasia, Sarcomatoid carcinoma, Pseudophaeochromocytoma, and Coronary no-reflow phenomenon had fewer reports, their signal strengths were strong, necessitating further attention.

Discussion
Benzodiazepines (BZDs), derived from 1,4-benzodiazepine, play a pivotal role in the alleviation and treatment of emotional anxiety, hyperactive reactions, insomnia, and epilepsy.They are currently the most widely used and longest-standing drugs for insomnia treatment.The primary mechanism of these drugs is by acting on the reticular structure of the brainstem and the limbic system, enhancing the affinity between the inhibitory neurotransmitter GABA and its respective receptors, thus inducing a suppressive effect on the central nervous system.Alprazolam, introduced to the U.S. market in 1981, is a medium-acting benzodiazepine.It possesses various effects such as anti-anxiety, anti-convulsion, and anti-depression, making it one of the most extensively used BZDs.Past researches, via case reports, systematic reviews, prescription monitoring, and clinical trials, have primarily studied and evaluated the adverse reactions related to Alprazolam.
Previous case reports on Alprazolam's adverse reactions mainly include allergic reactions, addiction, withdrawal responses, short-term memory loss, sleepwalking, muscle weakness, mental disorders, frequent urination, bloody lactation, gum overgrowth, agitation, abnormal behaviors, lethal overdose, dose-dependent orgasmic disorders, and acute angle-closure glaucoma 16 .Additionally, studies indicated that women taking Alprazolam during the first three months of pregnancy may increase the risk of congenital anomalies [17][18][19] .Nursing mothers consuming Alprazolam might lead to withdrawal symptoms and mild drowsiness in infants.Consuming Alprazolam during pregnancy might be linked to inguinal hernia, fetal deformities, and neonatal withdrawal syndrome, while its use during breastfeeding could cause mild drowsiness and withdrawal symptoms in infants.This research deeply analyzes the AE report data of Alprazolam to gain a more comprehensive understanding of its safety and the overview of AEs, providing a foundation for further risk management and clinical practice.

Report trends and patient characteristics analysis
This study delved into the AE reports from 2004 to 2023, especially focusing on reports where Alprazolam was the primary suspected drug.The results unveiled a series of noteworthy phenomena and trends.Firstly, in terms of the number of AE reports, there's an annual increase in reports related to Alprazolam.Specifically, there were marked surges in 2015, 2018, 2019, and 2020.This trend hints at the rising societal and medical institutional concerns about the safety of Alprazolam.It might also suggest a broadening usage scope of this drug or its association with more complex and severe adverse reactions.Secondly, the gender and age distribution in the reports is intriguing.Females dominate the AE reports for Alprazolam 20 .This could imply that females might be more susceptible to Alprazolam's adverse effects or are more inclined to report these events.The most common age group in these reports is between 18 to 45 years, typically considered the most socially and professionally active cohort.Hence, these adverse reactions could severely impact their work and social lives.

Existing adverse reactions
The AEs primarily associated with Alprazolam center around Psychiatric disorders, encompassing Drug abuse, Completed suicide, and Drug dependence.Issues of Drug abuse and Drug dependence hint at the potential addictiveness of Alprazolam, posing risks to patient safety.Of particular concern are suicide-related events such as Completed suicide and Suicidal ideation.This aligns with previous research, emphasizing the need for  heightened vigilance regarding a patient's mental well-being while on Alprazolam, coupled with corresponding preventive measures.Beyond Psychiatric disorders, Nervous system disorders also stake a claim in Alprazolam's list of adverse reactions.This includes Somnolence, Coma, and Confusional state.Such reactions could be life-threatening, especially when driving or operating machinery.Injury, poisoning, and procedural complications emerge as another area of concern, especially for long-term Alprazolam users.Such irregularities could lead to grave health issues, necessitating routine monitoring.

New adverse reactions and potential mechanisms
Risk signal analyses unveil various aspects warranting further research.While there's a plethora of signals regarding General disorders and administration site conditions, and Injury, poisoning and procedural complications, the medicine's documentation doesn't explicitly cite these adverse reactions.This suggests that both doctors and patients might lack adequate awareness and vigilance towards these latent risks.
Signal strength analyses further expose several potential adverse reactions not documented in Alprazolam's instructions.These newfound adverse reactions pertain to the cardiovascular system and platelet function, including Benzodiazepine drug level abnormal, Acquired amegakaryocytic thrombocytopenia, and Papillary muscle disorder.The mechanisms underlying these reactions remain elusive, but they might involve drug metabolism, interactions, and intricate physiological processes.For instance, Benzodiazepine drug level abnormal might stem from interactions between Alprazolam and other drugs, affecting its metabolism-a facet demanding further illumination 21 .Meanwhile, Acquired amegakaryocytic thrombocytopenia might be linked to an undiscovered correlation between Alprazolam and platelet functionality, necessitating in-depth experimentation and study 22 .This research also identified rare but significant adverse reactions, namely Cutaneous T-cell dyscrasia, Sarcomatoid carcinoma, Pseudophaeochromocytoma, and the Coronary no-reflow phenomenon.For instance, Cutaneous T-cell dyscrasia might arise from Alprazolam's impact on the immune system 23 , and Sarcomatoid carcinoma could suggest that the drug indirectly affects biological pathways associated with cancer growth 24 .Pseudophaeochromocytoma might simulate some symptoms of pheochromocytoma by impacting the sympathetic nervous system.The Coronary No-reflow Phenomenon, a blood flow obstruction involving coronary arteries, may relate to Alprazolam's indirect effects on the cardiovascular system, particularly with high dosages or long-term use 25,26 .
Even though these adverse reactions are relatively less reported, given their severity and potential lifethreatening nature, they warrant further research and attention.These findings signal the need for vigilance, regarding not only common side effects of Alprazolam but also these rare yet potentially severe reactions.

Limitations
There were several limitations regarding to the FAERS database 27 .The primary limitation of this study is that all data come from a voluntary AE reporting database.The spontaneous reporting system suffers from a significant underreporting issue, therefore the results do not reflect the full picture of the actual adverse reactions occurring.The study did not consider medication dosage data, making it impossible to interpret the results in the context of drug dosage, thus presenting certain limitations.Hence, these results should be viewed as a preliminary understanding of Alprazolam's safety concerns and should not replace more systematic and rigorous clinical studies.Besides, without specific data to directly correlate the rise in adverse event reports with increased usage, it's difficult to confirm this relationship definitively.Nonetheless, these initial findings undeniably set a direction and foundation for deeper future research and discussions.

Conclusion
In summary, this research provides vital safety information for the clinical use of Alprazolam.It unveils various concerns and risks that demand further scrutiny.The risks of suicide and abuse remain areas of significant concern.The cardiovascular system, platelet function, and other serious and potentially fatal issues require further studies to determine their precise mechanisms and risk factors.Given Alprazolam's widespread use in treating anxiety, insomnia, and other symptoms, it's imperative to deeply understand and address these issues.Future studies should examine Alprazolam's safety concerns more comprehensively and meticulously, aiming for more precise clinical guidance.

Table 3 .
Constituent ratio of yearly data of AEs related to Alprazolam.

Table 4 .
The signal strength of AEs of Alprazolam at the SOC level.

Table 5 .
The top 30 adverse events of Alprazolam ranked by case reports.

Table 6 .
The top signal strength of AEs of Alprazolam ranked by EBGM at the PTs level.